NEW YORK—Stem cell-based disease models
enable scientists to study disease on a cellular and genetic level by taking cells from patients and reprogramming them into human-induced pluripotent stem
cells (hiPSCs), unspecialized cells that can differentiate into any kind of mature cell and renew themselves over long periods of time. A team from The Icahn School of Medicine at Mount Sinai working in the areas of schizophrenia, bipolar disorder and
autism found that despite the benefits of stem cell-based disease modeling, there are some rare mutations that cannot be recreated in generated stem cells.
This study, “Divergent Levels of Marker Chromosomes in an hiPSC-Based Model of Psychosis,” was published in Stem Cell Reports March 14.

The mutation they sought to model was present
in hiPSCs from a woman with bipolar disease with psychosis, and her son, who had been diagnosed with schizoaffective disorder. Both the mother and her son
presented with a very small extra chromosome, less that 1/10th the normal size, a microduplication of genes that is now being linked to
schizophrenia and bipolar disorders. The extra chromosomal fragment, which is known as a marker (mar) element, is considered an abnormally duplicated gene.
Mar elements appear in less than .05 percent of newborn infants, but more than 30 percent of individuals that present with such genetic mutations are
clinically abnormal. In addition, mar elements are far more likely to appear in patients with development delays.

“Our study describes how a complex chromosomal rearrangement genetically passed by a patient with psychosis to her affected son was not well
recreated in laboratory-produced stem cells,” said Dr. Kristen Brennand, associate professor of genetics and genomic sciences, neuroscience and
psychiatry at the Icahn School of Medicine, and the study’s senior investigator. “As stem cell biologists dive into studying brain disorders, we
all need to know that this type of rare mutation is very hard to model with induced stem cells.”

“We’re trying to show this is the rare example, that this can happen, so that all stem cell scientists will try to be as careful in the
future as we’re going to be going forward, knowing this is possible,” she adds.

The researchers tried,
for the first time, to engineer stem cells from adult cells with this type of mar defect, only to find that the mar element was often lost in the process of
reprogramming the stem cells. The mother’s cells were mosaic, in that some cells were normal while others had the extra mar chromosome, a condition the
team was able to replicate. But replicating that with the son’s cells was not as successful; while all of his cells should have had the mar element,
some of the reprogrammed stem cells lacked the extra chromosome fragment.

“I think mosaicism is fascinating;
the idea that your brain cells might be different than your blood cells, genetically, that makes all the questions that you could ask more difficult,”
Brennand tells DDNews. “It also means that some of your brain cells might be genetically different than others. It really makes the issues of
stem cell modeling difficult, because which ones are you modeling? It’s a fascinating question.”

“Unfortunately, the mutation in this cohort is so unstable that we haven’t figured out how to address it,” she continues. “So
the cells might sit in the freezer for a year or two until we have a better assay, a better way of working with them. We had hoped to use them to understand
how glycine metabolism contributes to disease, but it might be that we have to find another patient. We’re going to keep moving forward on
schizophrenia, but this particular family is a more difficult problem than we thought. Stem cell work’s only 10 years old, and every year we get better
and better at what we do, and in a few years maybe we’ll be ready for this tougher problem.”

In
addition to the Mount Sinai researchers, scientists from Baylor College of Medicine, Cold Spring Harbor Laboratory, McLean Hospital, Hoffmann-La Roche Ltd.
and The University of California, San Diego, contributed to this work.